Therapeutic targeting of NAMPT and its associated pathways in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a global health challenge that affects more than 700,000 people yearly and has a devastating five-year survival rate at <20%. Current standard of care treatment for HCC showed limited efficacy in patients, driving the need for a more effective targeted therapy. As the major metabolic hub of the body, the liver undergoes tremendous metabolic reprogramming during tumorigenesis. Such remodelling could result in the activation of new metabolic pathways, creating new adaptative mechanisms or cancer-specific dependencies that could be potentially targeted. To uncover clinically relevant cancer-specific metabolic targets, patient derived HCC models were generated and subjected to a high throughput metabolic screening. This revealed therapeutic vulnerability of a subset of HCC towards NAD metabolism and circadian rhythm related pathways, which are commonly dysregulated pathways in HCC. Understanding the mechanistic underpinning this highly unique and understudied pathway in HCC could have potential implications for novel treatment modalities in HCC.